POS0627 BLOOD-BASED PROTEIN BIOMARKERS ARE ASSOCIATED WITH SUBCLINICAL CARDIOVASCULAR ABNORMALITIES AS DEFINED BY CARDIOVASCULAR MAGNETIC RESONANCE IMAGING IN SYSTEMIC SCLEROSIS (SSc) PATIENTS
Authors: W. C. Cheung, R. Shukla, R. Dumitru, N. Black, B. Erhayiem, G. Fent, F. Del Galdo, C. Miller, D. Plant, S. Plein, M. H. Buch
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic sclerosis-primary heart involvement (SSc-pHI) accounts for up to one-third of SSc-related deaths and clinically apparent pHI portends poor outcome. Early detection of SSc-pHI is therefore crucial. We have previously shown cardiovascular magnetic resonance (CMR)-detected subclinical myocardial abnormalities. Identifying robust blood biomarkers of SSc-pHI would facilitate diagnostic testing, help to resolve the biological mechanisms underpinning SSC-pHI and potentially identify new targets for drug development. <h3>Objectives</h3> To identify protein biomarkers associated with subclinical cardiovascular abnormalities as defined by CMR measures in SSc patients, and predominant inflammatory and cardiometabolic pathways implicated. <h3>Methods</h3> Seventy-eight patients from CONVAS ('CONnective Tissue Disease and VASculitis Cohort') and ELCASA ('ELectrophysiology and CArdiac imaging in SclerodermA')1 study cohorts underwent CMR imaging. Using Olink Proximity Extension Assay, normalised protein expression (NPX) across cardiometabolic, cardiovascular II/III and inflammation panels was measured in these patients at the time of CMR. Generalised linear regression with Benjamini Hochberg correction for multiple testing was used to identify significant proteins associated with CMR parameters of myocardial oedema/fibrosis [native T1, myocardial extracellular volume (ECV) and late gadolinium enhancement (LGE)] and vascular stiffness [aortic distensibility]. Subsequently, an expanded protein-protein interaction (PPI) network was created using an induced network approach (String-DB) with k-means clustering applied to identify enriched functional clusters that were then subjected to Gene Ontology (GO) and KEGG enrichment analysis. <h3>Results</h3> Of 355 proteins analysed, 70 proteins were associated with myocardial tissue oedema/fibrosis (64 proteins; 26 positively, 38 negatively) and vascular stiffness (6 proteins; 2 positively, 4 negatively). 2 overlapping proteins that associated with focal (LGE) and diffuse fibrosis (ECV) were identified. *Proteins identified include those involved in coagulation cascade (estimate = -1.97, 95%CI = -3.63 to -0.31, adj.p = 0.039), carbohydrate binding and opsonisation activities (estimate = -1.31, 95%CI = -2.19 to -0.43, adj.p = 0.006); and cancer and neovascular inflammatory conditions (estimate = -75.79 95%CI = -119.81 to -31.76, adj.p = 0.002). K-means clustering of the expanded PPI network (enrichment p.value &lt; 1.0e-16) identified 4 clusters (Figure 1) with roles in TNF receptor superfamily binding and NF-kappa B signalling pathway (red); Vascular endothelial growth factor-activated receptor activity and Rap1 signalling pathway (yellow); IL-10 receptor activity and JAK-STAT signalling pathway (blue); and FGF activated class receptor binding and ErbB signalling pathway (green). Proteins associated with CMR detected subclinical myocardial tissue oedema/fibrosis mainly mapped to yellow and blue clusters. <h3>Conclusion</h3> In this first proteomic study of SSc-pHI, we have identified 70 protein biomarkers, with myocardial tissue oedema/fibrosis associated with inflammation and vascular pathways. The next step is to validate these proteins and test the utility of network proteins in an independent patient cohort that could aid detection and diagnosis of SSc-pHI. *Proteins names not disclosed as subject to Intellectual Property discussions via Innovation Factory, University of Manchester. <h3>Reference</h3> [1]Dumitru, R. B., et al (2021). Cardiovascular outcomes in systemic sclerosis with abnormal cardiovascular MRI and serum cardiac biomarkers. RMD open, 7(3), e001689. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.